Osteoporosis and Sarcopenia are diseases of bone and muscle loss that represent a major clinical problem in the aged population. These conditions often occur together, suggesting common pathogenic mechanisms and/or crosstalk between muscle and bone. Current treatment for osteoporosis target osteoclast or osteoblast activity to maintain bone mass, but the osteocyte has been overlooked. Exciting recent research has shown that osteocytes are major regulators of osteoblast and osteoclast function and that regulation of the Wnt/3-catenin pathway by osteocytes may play a central role in regulation of bone mass. Our laboratory has taken a unique approach to examining osteoblast-osteocyte interactions using fluorescence live imaging approaches in bone cell and organ culture models. We have shown that osteoblasts on the bone surface are motile cells and that assembly of ECM proteins In living osteoblasts is a highly dynamic process that is integrated with cell motility. We have also shown that Sclerostin and Wnts, both produced by osteocytes, can alter osteoblast motility and differentiated function. Building on these observations, this project will examine osteocyte control of osteoblast function from a dynamic perspective. The overall hypothesis is that osteocytes regulate bone mass through the Wnt/p-catenin signaling pathway by controlling the motile properties and differentiated function of osteoblasts and that this regulatory process is modulated by muscle- bone crosstalk and is impaired during aging, leading to a compromised skeleton. To address this hypothesis, live cell imaging techniques will be used in young and aged transgenic mouse models expressing fluorescent reporters for osteoblast and osteocyte lineages and GFP-tagged extracellular matrix proteins. The effect of modulation of osteocyte-produced Wnt and sclerostin will be investigated using inhibitors, gene silencing and transgenic approaches. To determine whether crosstalk from muscle alters osteocyte control of osteoblast function, in viti-o models of myoblast differentiation and transgenic and aged models of impaired or enhanced muscle function will be used. These studies may lead to the way to novel therapeutic approaches for preventing loss of bone and muscle mass in the elderly.